Correction of hypoalphalipoproteinemia in LDL receptor-deficient rabbits by lecithin : cholesterol acyltransferase

Familial hypercholesterolemia (FH), a disease caused by a variety of mutations in the low density lipopro- tein receptor (LDLr) gene, leads not only to elevated LDL- cholesterol (C) concentrations but to reduced high density lipoprotein (HDL)-C and apolipoprotein (apo) A-I concen- trations as well. The reductions in HDL-C and apoA-I are the consequence of the combined metabolic defects of in- creased apoA-I catabolism and decreased apoA-I synthesis. The present studies were designed to test the hypothesis that overexpression of human lecithin:cholesterol acyl- transferase (hLCAT), a pivotal enzyme involved in HDL metabolism, in LDLr defective rabbits would incr ease HDL-C and apoA-I concentrations. Two groups of hLCAT transgenic rabbits were established: 1 ) hLCAT 1 /LDLr het- erozygotes (LDLr 1 / 2 ) and 2 ) hLCAT 1 /LDLr homozygotes (LDLr 2 / 2 ). Data for hLCAT 1 rabbits were compared to those of nontransgenic (hLCAT 2 ) rabbits of the same LDLr status. In LDLr 1 / 2 rabbits, HDL-C and apoA-I con- centrations (mg/dl), respectively, were significantly greater in hLCAT 1 (62 6 8, 59 6 4) relative to hLCAT 2 rabbits (21 6 1, 26 6 2). This was, likewise, the case when hLCAT 1 / LDLr 2 / 2 (27 6 2, 19 6 6) and hLCAT 2 /LDLr 2 / 2 (5 6 1, 6 6 2) rabbits were compared. Kinetic experiments dem- onstrated that the fractional catabolic rate (FCR, d 2 1 ) of apoA-I was substantially delayed in hLCAT 1 (0.376 6 0.025) versus hLCAT 2 (0.588) LDLr 1 / 2 rabbits, as well as in hLCAT 1 (0.666 6 0.033) versus hLCAT 2 (1.194 6 0.138) LDLr 2 / 2 rabbits. ApoA-I production rate (PR, mg ? kg ? d 2 1 ) was greater in both hLCAT 1 /LDLr 1 / 2 (10 6 2 vs. 6) and hLCAT 1 / LDLr 2 / 2 (9 6 1 vs. 4 6 1) rabbits. Significant correlations ( P , 0.02) were obser ved be- tween plasma LCAT activity and HDL-C ( r 5 0.857), apoA-I FCR ( r 5 2 0.774), and apoA-I PR ( r 5 0.771), while HDL-C correlated with both apoA-I FCR ( 2 0.812) and PR (0.751). In summary, these data indicate that hLCAT overexpression in LDLr defective rabbits increases HDL-C and apoA-I concentrations by both decreasing apoA-I catab- olism and increasing apoA-I synthesis, thus correcting the metabolic defects responsible for the hypoalphalipopro- teinemia observed in LDLr deficiency.— Brousseau, M. E., J. Wang, S. J. Demosky, Jr., B. L. Vaisman, G. D. Talley, S. San- tamarina-Fojo, H. B. Brewer, Jr., and J. M. Hoeg. Correction of hypoalphalipoproteinemia in LDL receptor-deficient rab- bits by lecithin:cholesterol acyltransferase. J. Lipid. Res. 39: 1558-1567.